Dual-tracer PET/CT protocol with [18F]FDG and [68Ga]Ga-FAPI-46 outperforms single-tracer PET/CT with [18F]FDG in different cancer types, resulting in larger functional and gross tumor volume

Strahlentherapie und Onkologie https://doi.org/10.1007/s00066-023-02117-2 ORIGINAL ARTICLE Dual-tracer PET/CT protocol with [18F]FDG and [68Ga]Ga-FAPI-46 outperforms single-tracer PET/CT with [18F]FDG in different cancer types, resulting in larger functional and gross tumor volume Simone Wegen1 · Jasmin Weindler2 · Conrad-Amadeus Voltin2 · Lutz van Heek2 · Klaus Schomäcker2 · Thomas Fischer2 · Simone Marnitz1 · Carsten Kobe2 · Alexander Drzezga2 · Katrin S. Roth2 Received: 4 April 2023 / Accepted: 5 July 2023 © The Author(s) 2023 Abstract Purpose Fibroblast activation protein (FAP) detected by positron-emission tomography (PET) using fibroblast activation protein inhibitor (FAPI) appears to be a promising target for cancer imaging, staging, and therapy, providing added value and strength as a complement to [18F]fluorodeoxyglucose (FDG) in cancer imaging. We recently introduced a combined single-session/dual-tracer protocol with [18F]FDG and [68Ga]Ga-FAPI for cancer imaging and staging. Malignant tissue visualization and target-to-background uptake ratios (TBRs) as well as functional tumor volume (FTV) and gross tumor volume (GTV) were assessed in the present study with single-tracer [18F]FDG PET/computed tomography (CT) and with dual-tracer [18F]FDG&[68Ga]Ga-FAPI-46 PET/CT. Methods A total of 19 patients with head and neck and gastrointestinal cancers received initial [18F]FDG-PET/CT followed by dual-tracer PET/CT after additional injection of [68Ga]Ga-FAPI-46 during the same medical appointment (on average 13.9 ± 12.3 min after injection of [18F]FDG). Two readers visually compared detection rate of malignant tissue, TBR, FTV, and GTV for tumor and metastatic tissue in single- and dual-tracer PET/CT. Results The diagnostic performance of dual-tracer compared to single-tracer PET/CT was equal in 13 patients and superior in 6 patients. The mean TBRs of tumors and metastases in dual-tracer PET/CTs were mostly higher compared to single-tracer PET/CT using maximal count rates (CRmax). GTV and FTV were significantly larger when measured on dual-tracer compared to single-tracer PET/CT. Conclusion Dual-tracer PET/CT with [18F]FDG and [68Ga]Ga-FAPI-46 showed better visualization due to a generally higher TBR and larger FTV and GTV compared to [18F]FDG-PET/CT in several tumor entities, suggesting that [68Ga]Ga-FAPI-46 provides added value in pretherapeutic staging. Keywords Dual-tracer PET/CT · Gross tumor volume · Functional tissue volume · FDG · FAPI Introduction The authors S. Wegen and J. Weindler as well as A. Drzezga, and K.S. Roth contributed equally to the manuscript.  Dr. Katrin S. Roth 1 Department of Radiation Oncology, Cyberknife and Radiotherapy, Faculty of Medicine, University Hospital Cologne, Cologne, Germany 2 Department of Nuclear Medicine, Faculty of Medicine, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany Malignant tumors mostly consist of two compartments: the tumor microenvironment and malignant cells. The transmembrane glycoprotein fibroblast activation protein (FAP) is highly expressed in the tumor microenvironment/stroma, cancer-associated fibroblasts (CAFs), and pericytes, accounting for the predominant portion of the tumor mass. However, it is not expressed directly on tumor cells, vascular epithelial cells, or inflammatory cells [1]. Several in vivo and histological studies found high expression of FAP in the majority of human epithelial malignancies [2–4]. Due to its increased expression in the stroma of tumors and of metastases, and given the potential impact of the K Strahlentherapie und Onkologie tumor stroma on treatment outcome, FAP was identified as a new and promising target for tumor detection and therapy [5, 6]. Recent studies with quinolone-based positronemission tomography (PET) tracers, acting as FAP inhibitors (FAPI), showed promising results with [68Ga]GaFAPI-PET for diagnosis and staging of various cancers [3, 7], with comparable or even better results in primary tumor detection than [18F]fluorodeoxyglucose(FDG)-PET/ computed tomography (CT) [8]. Compared to [18F]FDG, [68Ga]Ga-FAPI shows a fast tumor uptake [8] with an equal or higher tumor to background ratio [9] and low uptake in most healthy organs including brain and liver, allowing the detection of malignant lesions in these organs [10, 11]. A recent study in patients with head and neck tumors (HNT) showed significantly larger gross tumor volumes (GTVs) measured with [68Ga]Ga-FAPI-46-PET/CT compared to [18F]FDG-PET/CT [12] and an accurate tumor delineation with [68Ga]Ga-FAPI-PET/CT, matching with tumor clipping [13]. In addition, a recently published study points to the potential of FAPI-PET/CT for response prediction in patients with esophageal cancer [14]. This is in line with a meta-analysis evaluating FAP expression in various tumors and showing significant correlation between high FAP expression and tumor progression [15]. As recently described, there is no gold standard for target volume delineation in esophageal cancer and parameters predicting a response to radiotherapy are missing [16]. For head and neck cancer, the target volume delineation of tumors with [18F]FDG-PET/CT has high concordance with the histopathological tumor extent, but the small superficial tumor parts and micrometastases are not reliably localized [16]. In esophageal cancer for example, the treatment decision between neoadjuvant versus definitive radiotherapy was shown to lead to significant differences in locoregional control and overall survival for patients with advanced disease [17]. Therefore, and since it was shown that chemoradiation can lead to changes in the immune cell composition and, consecutively, in the tumor microenvironment in cervical cancer [18], studies displaying and in the future treating different compartments of the tumor are necessary. Due to tumor heterogeneity also given the different tumor compartments, exclusive imaging of the tumor microenvironment with [68Ga]Ga-FAPI-PET/CT may not be universally recommended or always sufficient in the diagnostic workup of malignant diseases. With regard to the different mechanisms of action and tracer retention, [18F]FDG and [68Ga]Ga-FAPI-PET/CT may represent complementary tools, capturing different aspects of tumor biology. Since [18F]FDG-PET/CT still represents a well-established standard for diagnostic imaging in many cancer types, and for guiding treatment planning, we recently established a single-session/dual-tracer PET/CT protocol for cancer staging prior to radiotherapy consisting of an [18F]FDG-PET/CT K and a subsequent repeat scan following the injection of [68Ga]Ga-FAPI [19]. In a preliminary study testing this protocol, dual-tracer PET/CT demonstrated equal and, in some respects, superior performance in lesion detection compared to each single-tracer PET/CT. The aim of the present study was to confirm the feasibility and explore the potential of dual-tracer PET/CT by investigating the pe (...truncated)